By whatever criterion one uses- loss of life, loss of productivity, family disintegration, mental anguish, health care costs, costs at all levels of government- cocaine abuse has posed a significant problem. Adding further to the dimension of this problem is the birth of "crack" cocaine babies and the AIDS scourge. The cost of this multifaceted problem to this nation, in human and economic terms, is almost beyond comprehension. One particularly important characteristic of drug dependence, regardless of substance, is the pattern of multiple drug use. A consequence of that practice is the potential for interactions among the abused substances which can further exacerbate a toxic state or affect the dependence liability of any or all of the abused substances. In the case of cocaine, what is particularly remarkable is the degree of ethanol coingestion. Several surveys have indicated a high incidence of co-use of these two drugs. It is also clear that this coingestion results in increased pharmacologic response and it results in far greater risk of death compared to cocaine use alone. The reason(s) for these observations has not been firmly established but at least two possibilities exist to explain the ethanol-enhanced response to cocaine. The first involves the alteration in the disposition of cocaine per se and, in concert with this, is the alteration of the profile of active or toxic metabolites. One particularly interesting aspect of the latter possibility is the recent recognition of the formation of an active metabolite, cocaethylene (ethyl cocaine), resulting from the interaction between ethanol and cocaine. The research program outlined here has been designed to quantitate the disposition kinetics of cocaine in the absence and presence of ethanol. This will be done in rats under acute and chronic dosing paradigms. In addition, we propose to examine the response (locomotor activity) to cocaine and metabolites in the absence and presence of ethanol. These data will be used to develop a combined pharmacokinetic-pharmacodynamic model to explore the cocaine-ethanol interaction.